Extrusion processing to produce controlled release pharmaceutical preparations is perceived as having the advantages of reducing the process steps needed to manufacture the preparations as well as enabling the manufacture to be carried out on a continuous or semi-continuous basis. Such extrusion of a softened blend including an active agent is usually referred to as melt extrusion. The backbone of melt extrusion technology is the application of thermoplastic materials which act as binders for embedded drugs in solution or dispersion form within a matrix. Thermoplastic polymers with low glass transition temperatures (Tg) are preferred for processing by melt extrusion. Lower processing temperatures are preferred with respect to the stability of heat sensitive drugs and other necessary excipients. Polymer glass transition temperatures can be reduced to facilitate processing at lower temperatures by optional addition of plasticisers.
By selection of suitable polymers and additives, melt extrusion technology can be used both to enhance the solubility, and subsequently the bioavailability, of poorly water soluble drugs as well as to retard drug release of moderate to highly water soluble drugs for controlled release products.
Multiparticulates of uniform dimensions with modified drug release properties can readily be manufactured by such melt extrusion technology.
Illustratively WO 96 14058 describes a melt extrusion method of preparing a sustained-release pharmaceutical extrudate suitable for oral administration. The method comprises:
blending a therapeutically active agent together with (1) a material selected from the group consisting of alkylcelluloses, acrylic and methacrylic acid polymers and copolymers, shellac, zein, hydrogenated castor oil, hydrogenated vegetable oil, and mixtures thereof and (2) a fusible carrier selected from the group consisting of natural or synthetic waxes, fatty acids, fatty alcohols, and mixtures thereof; said retardant material having a melting point between 30-200° C. and being included in an amount sufficient to further slow the release of the therapeutically active agent;
heating said blend to a temperature sufficient to soften the mixture sufficiently to extrude the same;
extruding said heated mixture as a strand having a diameter of from 0.1-3 mm; cooling said strand; and dividing said strand to form non-spheroidal multi-particulates of said extrudate having a length from 0.1-5 mm; and
dividing said non-spheroidal multi-particulates into unit doses containing an effective amount of said therapeutically active agent, said unit dose providing a sustained-release of said therapeutically active agent for a time period of from about 8 to about 24 hours.
In the worked Examples used to describe this method, stearic acid is employed as a lubricant in the extruded formulation. For instance in Examples 1 to 6 the formulation contains 20% by weight of stearic acid, the controlled release material being variously ethylcellulose and Eudragit RS PO. Extrusion temperatures are in the range of 85° C. to 105° C.
A disadvantage of thermoplastic material, however, is that the Tg may be too high to enable processing to be carried out at temperatures low enough to avoid degradation of the active ingredient and/or excipients.
One solution used to mitigate this problem has been to add excipient material which has a plasticising effect and thus lowers the Tg of the thermoplastic polymer. It serves to reduce cohesion by providing internal lubrication of the polymer.
In our co-pending PCT patent application PCT WO 2005/000310 of 27 Jun. 2004 entitled Multiparticulates, we describe examples of formulations in which relatively high levels of a plasticiser, especially stearyl alcohol, and a lubricant, namely stearic acid, are used together with acrylic copolymers and oxycodone hydrochloride as active ingredient. The temperatures required to extrude these formulations are typically in the range 75° C. to 95° C. At such temperatures it was found that the extrudate had good chemical stability after storage under accelerated storage conditions (40° C./75% RH) but the release rate of the active agent from the formulation was found in in vitro testing to change over time. Initially, stearic acid was found to have an influence on release rates in buffers of different pHs, and therefore a search was made for alternative lubricants. Glyceryl behenate was found to be effective.
A need remains for the availability of new processes and formulations which will allow the extrusion of controlled release formulations at relatively low to moderate temperatures which do not give rise to the risk of degradation of heat sensitive or heat labile active ingredients or other components of the formulation, for example in the range 75° C. to 95° C., as well as allowing the extrusion of formulations from which conventional components which may result in release rate instability can be excluded.